Delivery of a therapeutic transgene to cells widely distributed throughout the body (such as skeletal muscle, nerves, skin, bone or fat) via a systemic route has traditionally proven ineffective. From attempts to utilize the intravascular route for systemic delivery to skeletal muscle fibers, it has been determined that the vascular endothelium represents the critical barrier to dispersion of vectors beyond the bloodstream. Early approaches attempting to overcome cellular barriers utilized methods of mechanical disruption of cell membranes (e.g. electrical field poration, high energy ultrasound, or extra-cellular matrix degrading agents) that were accompanied by considerable tissue damage. These methods are presently considered either unsuitable for clinical development, or present limited potential for scaling to human application. More recent strategies employed to breach the endothelial barrier in vivo, rely on dramatically elevated hydrostatic pressure, coupled with pre-treatments incorporating potent pharmacological agents to increase the blood flow within a limited number of select target tissues, and enhance local vascular permeability (typically papaverine and histamine, respectively).
The clinical potential of these methodologies is severely limited owing to the considerable risks of adverse effects imposed on frail patients by the current techniques (e.g. acute hypertension-related events, profound acute anaphylaxis). Furthermore, target tissues have previously been isolated from the circulation via occlusion of major arteries and veins, with support via external artificial circulation, which requires invasive procedures, particularly for some tissues that are difficult to access. For instance, transduction of the myocardium has necessitated circulatory isolation by highly invasive surgical means to administer the aforementioned interventions. The combined risks associated with highly invasive procedures incorporating intra-vascular pressure elevation and pharmacological agents with established toxic potential represent significant shortcomings to the realization of an efficacious procedure that is safe for systemic administration and body-wide dispersion of therapeutic genetic components.
Therefore, what is needed are compositions and methods that allow for systemic nucleic acid sequence delivery without the need for systemic administration aids such as increased vascular pressure, isolated blood vessels or organs, or extracorporeal support for a subject.